Thursday, 24 January 2013

Guest post: FUMADERM and PML – can we make conclusions for BG12?

#MSBlog: What does Prof. Gold, the PI on the BG12 programme, have to say about Fumaderm and PML?

"In response to the intense interest on the blog concerning Fumaderm and PML and its possible implications for BG12, we invited Professor Doctor Ralf Gold to contribute a guest post on this topic! I hope it answers some of your questions. It has mine!"

Recently two cases of PML unfolding under monotherapy of psoriasis with Fumaderm have been observed, and await publication in a major journal. Fumaderm is the old mixture of dimethylfumarate and three different salts of ethylhydrogenfumarate, licensed since 20 years in Germany with more than 170.000 patient years of experience.

The German case is very well known to me: a dermatologist had initiated fumarate treatment in 2007 in a 71 year old male, and since summer 2009 this patient had developed marked lymphopenia (low lymphocyte count; a type of whit blood cell) with relative values below 10% and absolute lymphocyte counts around 300-400/µl (normal levels are usually greater than 1500//µl). According to the SPC (Summary of Product Characteristics)of Fumaderm this should have resulted in immediate cessation of treatment, and subsequent dose reduction after normalization of lymphocyte values. Of note, after PML occurred Fumaderm was stopped immediately by the neurologists. Yet it took over 12 months until lymphocyte values of this patient came back into lower normal range.

What does this tell us? Although dimethylfumarates (BG12) were completely safe in controlled MS studies, a minimum of blood controls every 4-6 weeks as detailed in the SPC for Fumaderm should also be considered in this monotherapy. If needed fumarate dose may be adjusted – there may be rare genetic variants where higher systemic fumarate levels are achieved in patients. There is no doubt from recent research data that fumarates impact the immune system, and persistent violation of prescription rules can cause problems as in any immunoactive therapy. In view of the high efficacy of BG12 in phase III trials I feel that a minimum of safety controls is justified and should be performed.

Of course we now have to wait if the drug receives approval for MS therapy by regulatory authorities, and which specific measures will be implemented in the SPC.

What is the relevance of Fumaderm 170k patient-years? As I understand few patients have been on a continues daily use of Fumaderm for more than 1 year, and what we are worried of is the long-term treatment risks associated with BG-12.

Funny to see the so called clinical trials of Fumaderm. I understand why Biogen try to distance themselves from Fumaderm as much as possible when getting questions if the Fumaderm data is part of the registration file at the EMA and the FDA.

I attach a link to a page that give some more color to BG-12 and its characteristics.

I am currently taking fumaderm, I ask my dermatologist how long I can expect to stay on it for and he told me that fumaderm has been available in Ireland for 13 years and he has several patients who have been on it for 13 years.

Some details about studies with Fumaderm. They don't seem to be very reliable, at least not when reading the comments..

" LimitationsEvidence for the efficacy and safety of Fumaderm® is limited by the lack of controlled trial data, especially investigating long-term use or comparison with other systemic therapies. Studies have not used recommended combinations of outcome measures for psoriasis therapies, generally involve small numbers of patients and many poorly document their methods and findings. Patients with serious co-morbidity have been excluded from all controlled studies to date. Paediatric data are lacking. "

Safety dataAdverse effects are common when starting Fumaderm® and lead to discontinuation and/or non-compliance in 30 to 40% of patients [2]. Two thirds of patients experience gastrointestinal symptoms of diarrhoea, abdominal pain and flatulence and one third report facial flushing lasting minutes to hours, sometimes associated with headache [2,4]. These adverse effect rates occur despite initial use of low doses and gradual dose increases as recommended by the manufacturer [3]. Dose reduction may alleviate symptoms but Fumaderm® should be stopped if no improvement is seen [2]. Fumaderm® can be stopped abruptly as relapse or rebound phenomena do not occur [12,28].

Reversible leucopenia, lymphopenia and transient eosinophilia are also frequently observed [2]. Leucopenia occurs in a quarter of patients [8,29]. A reduction in lymphocyte count occurs in around 70% of patients [6,8,25,29] and can exceed 50% in about 10% of patients [4]. The dose of Fumaderm® should be reduced if lymphocytes fall below 0.5x109/L or leucocytes fall below 3.0x109/L; if blood counts improve, treatment can continue at the reduced dose, but otherwise Fumaderm® should be stopped [9]. It has been reported that patients with lymphopenia are significantly more likely to show improvement in psoriasis than those whose lymphocyte count stays within the normal range [6,22,24]. Eosinophilia occurring between the fourth and tenth week of treatment [28], in up to a third of patients, generally lasts for one to two months and resolves without intervention [6-8,14,17,22-24,29]. The clinical significance of these changes is not known but long-term follow-up of patients with haematological abnormalities does not suggest they are at an increased risk of infection or cancer [22,29].

Observational studies following patients for up to 14 years do not indicate that Fumaderm® causes serious or permanent adverse effects [6-8,18,19,22,29]. There have been rare case reports of patients developing acute renal failure or proteinuria when given Fumaderm® [1,2,4,10]. Some studies report raised serum creatinine and/or the presence of urinary protein in up to 30% of patients; in the majority of patients the changes were transient and needed no intervention [8,14,17,19,25,27,29]. Transient and/or reversible increases in liver enzymes and hypercholesterolaemia have also been reported [2,6-8,14,17,22,29]. It is recommended that kidney and liver function should be monitored regularly during treatment [3].

" Monitoring requirement for BG12? An investor forwarded to us a web blog with an entry from Dr. Ralf Gold where he discusses two cases of PML. Dr. Gold believes the PML cases are associated with the impact of BG-12 on the immune system and that lymphocyte count should be performed every 4-6 weeks (as in Fumaderm) to ensure immunosuppression is not a problem. Given Dr. Gold's heavy involvement with the BG-12 program (first author on the NEJM paper), we suspect some sort of requirement of this nature is more likely. Any concern around B-G12 safety and ongoing monitoring requirement would reasonably help Copaxone. See http://multiple-sclerosis-research.blogspot.com/2013/01/guest-post-fumaderm-and-pml-can-we-make.html

~100 g of fumaric acid cost ~$5. One can make ~100 g of dimethyl ester of fumaric acid in a day using small amounts of methanol and hydrochloric acid (they cost close to nothing). I refuse to understand how Biogen Idec can make any money on this drug when almost anybody (here or abroad) can make the amount of this so-called "drug" (it's a food additive!) they charge $55K/year for, so easy...

Interesting that Fumaderm is used for treating psoriasis and so is vitamin d. Are the causes of psoriasis and MS linked? Or do both vitamin d and Fumaderm damp down an over active immune system. If so a high vitamin d blood level would be a more risk averse initial strategy, as the side effects (high blood calcium levels) can easily be measured.

I agree with the post above about the cost. I have started an email campaign on this. Everyone please do your research and contact your government official, and hell even your insurance companies. My Neurologist was very very disappointing when I told him what the price point will be. He said there will be a push back from Neuro's on this and he simple won't prescribe it. Hell even contact your insurance company and tell them to take a very very hardline when negotiating price with Biogen. This is a very simply compound they have developed. Actually they didn't develop it they acquired the company that did. They just had the foresight to see where it could go. Kudos to Biogen for investing so much in bringing it to market for sure. If insurance companies negotiate the price even down 20% it is still way more than Avonex. Which by the way Biogen was able to increase the patent on until 2028 I think. I do not have a personal vendetta against Biogen. However I do have Ms and this unjustifiable and unethical pricing has to stop. Only we as a people can band together and push back. If Biogen has no customers where does that leave them? I'll tell you with millions invested in a drug thats too expensive to buy and a bunch of angry shareholders!!

The second article states the woman had been given a "probable diagnosis of MS" due to her left sided hemiparesis. When PML develops it can sometimes appear symptomatically similar to MS. In this case, it appears the patient did not have MS, but rather PML. The author feels that the long term treatment with Psorinovo was the reason for the lymphopaenia. The author also states that lymphopaenia is a known side effect for treatment with Psorinovo in some patients. It is suggested that patients treated with fumarates be monitored for such side effects. Clearly someone wasn't being monitored as a CBC would have detected this problem much earlier, and may have likely prevented this case from occuring.

Two cases of PML against 170K patient years is not yet a scientific and statistical case. It is more a rare occasion.The PML case on Psorinovo, which is the slow release variant of dimethyfumarate use (it's suits me very good against my PsA), is due to low lymphocyte counts. This is a possible side effect of all dimethylfumarate use, be it Psorinovo, Fumaderm or Tecfidera or other variants. There are warnings that come with the use of DMF's, which state that regular (every 6 months) blood counts have to be done. If lymphocytes fall below the reference values, use of DMF should be stopped. It is not the medication that cause PML it is the low lymphocytes that cause it. The same is seen when using methotrexate, where even hundreds of cases of PML are known due to low lymphocytes. The woman, I happen to know her, is aware that it is caused by a too low count and is contact with her doctors on why she was not warned.

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